Presynaptic FMRP and local protein synthesis support structural and functional plasticity of glutamatergic axon terminals

Learning and memory critically rely on long-lasting, synapse-specific modifications. While postsynaptic forms of plasticity typically require local protein synthesis, whether and how local protein synthesis contributes to presynaptic changes remains unclear. Here, we examined the hippocampal mossy fiber (MF)-CA3 synapse which expresses both structural and functional presynaptic plasticity. We report that MF boutons synthesize protein locally and contain ribosomes. Long-term potentiation of MF-CA3 synaptic transmission (MF-LTP) was associated with translation-dependent enlargement of MF boutons. Moreover, increasing in vitro and in vivo MF activity enhanced protein synthesis in MFs. Remarkably, deletion of presynaptic Fragile X mental retardation protein (FMRP), an RNA-binding protein expressed in MF boutons and previously implicated in local postsynaptic protein synthesis-dependent plasticity, blocked structural and functional MF-LTP, suggesting that FMRP is a critical regulator of presynaptic function. Thus, presynaptic FMRP and protein synthesis dynamically control presynaptic structure and function in the mature brain. Highlights In Brief Monday et al. report that FMRP and protein synthesis in hippocampal mossy fiber boutons mediate functional and structural presynaptic plasticity. ### Competing Interest Statement The authors have declared no competing interest.